Mixtures for treating hypercholesterolemia

ABSTRACT

Psyllium gum and polyol polyesters are administered orally to reduce blood cholesterol levels.

TECHNICAL FIELD

The present invention relates to methods and compositions for reducingblood cholesterol levels by oral administration of psyllium derivativesand polyol polyesters.

BACKGROUND OF THE INVENTION

High blood cholesterol (hypercholesterolemia) is recognized as being arisk factor in cardiovascular disease which comprises a major healthcare problem, today. Epidemiological studies have demonstrated that,with few exceptions, populations consuming large quantities of saturatedfat and cholesterol have a relatively high concentration of serumcholesterol and a high mortality rate from coronary heart disease. Whileit is recognized that other factors can also contribute to thedevelopment of cardiovascular disease, there appears to be a causalrelationship between the concentration of serum cholesterol, in whichhypercholesterolemia results in the accumulation of undesirable amountsof cholesterol in various parts of the circulatory system(arteriosclerosis) or in soft tissues (xanthomatosis), and coronarydisease and coronary mortality rates.

A variety of dietary and drug regimens have been suggested foralleviating or preventing hypercholesterolemia. However, many of thesehave undesirable side effects or give suboptimal results. Accordingly,the search for materials which reduce blood cholesterol has continued.

In the present invention, nonabsorbable, nondigestible polyesters areused in combination with psyllium derivatives as orally-administeredcholesterollowering compositions. In one mode, the compositions hereinare additionally fortified with fat-soluble vitamins.

BACKGROUND ART

J. E. Garvin, D. T. Forman, W. R. Eiseman, and C. R. Phillips, Proc.Soc. Exp. Biol. Med., 120, 744 (1965) describe the administration ofpsyllium (as METAMUCIL brand laxative) to human volunteers, resulting ina reduction in blood cholesterol levels. Also, see Forman, et al, ibid127, 1060-1063 (1968).

There are a considerable number of United States patents relating to theuse of nonabsorbable, nondigestible polyol polyesters of the typeemployed herein as cholesterol lowering agents. See, especially, U.S.Pat. Nos. 3,600,186; 4,005,195; 4,005,196 (includes fat-solublevitamins); 4,034,083 (with fat-soluble vitamins); in various foodcompositions, e.g., U.S. Pat. Nos. 4,368,213; 4,461,782; 3,579,548; andin pharmaceutical products, e.g., U.S. Pat. Nos. 3,954,976; 4,241,054;4,264,583; and 4,382,924. Manufacturing processes for the polyolpolyesters are described in U.S. Pat. Nos. 3,963,699; 4,517,360; and4,518,772. All of these patents are incorporated herein by reference.

Psyllium derivatives (also referred to as "gums" or "hydrophilicmucilloids") of the type employed herein are known commercially asMETAMUCIL brand laxative and are described in Goodman and Gilman, ThePharmacologic Basis of Therapeutics 5th Ed. 979 (1975). See also U.S.Patents 3,455,714 and 4,321,263.

SUMMARY OF THE INVENTION

The present invention encompasses orally-administered compositions ofmatter for reducing blood cholesterol levels in humans or lower animals,comprising a mixture of:

(a) psyllium seed gum or source of psyllium seed gum; and

(b) a nonabsorbable, nondigestible polyol polyester.

The invention also encompasses a method for reducing blood cholesterolin a patient (including both humans and lower animals) in need of suchtreatment, comprising orally administering to said patient a safe andeffective amount of:

(a) psyllium seed gum or a source of psyllium seed gum; and

(b) a nonabsorbable, nondigestible polyol polyester; or

(c) mixtures of (a) and (b).

The compositions herein can be provided in bulk form as granules, or inunit dosage forms such as tablets, capsules, effervescing granules ortablets, and the like. The compositions can contain various flavorings,extenders, tableting aids, and the like, well-known to formulators ofpharmaceutical products.

In an optional embodiment, the compositions herein can be fortified withfat-soluble vitamins, since the polyol polyesters can undesirablydeplete the body's stores of these vitamins.

All percentages, ratios and proportions herein are by weight, unlessotherwise specified.

DETAILED DESCRIPTION OF THE INVENTION

The psyllium gum used in the practice of this invention comes frompsyllium seed, from plants of the Plantago genus. Various species suchas Plantago lanceolate, P. rugelii, and P. major, are known. Commercialpsyllium includes the French (black; Plantago indica), Spanish (P.psyllium) and Indian (blond; P. ovata). The gum content of the psylliumvaries: French psyllium, 11.8%, Indian psyllium, 30.9%; and Germanpsyllium, 11.5%. Indian (blond) psylllium is preferred for use herein.

The psyllium gum (or "hydrophilic mucilloid") is located in the seedcoat, from which it is readily extractable by water. Thus, intact ormacerated seeds can be used in the practice of this invention; however,it is more typical to remove the seed coats from the rest of the seedby, for example, slight mechanical pressure, and then to use only thecoats as a source of the gum. In the practice of the present inventionit is convenient and typical to use macerated seed coats in the finalformulation as the source of the psyllium seed gum, but, in analternative procedure, the seed coats are extracted with water to removethe desired gum for use in the compositions and methods herein.

The nonabsorbable, nondigestible polyol polyesters (or, simply,polyesters) employed in this invention comprise certain polyols,especially sugars or sugar alcohols, esterified with at least four fattyacid groups. Accordingly, the polyol starting material must have atleast four esterifiable hydroxyl groups. Examples of preferred polyolsare sugars, including monosaccharides and disaccharides, and sugaralcohols. Examples of monosaccharides containing four hydroxyl groupsare xylose and arabinose and the sugar alcohol derived from xylose,which has five hydroxyl groups, i.e., xylitol. (The monosaccharide,erythrose, is not suitable in the practice of this invention since itonly contains three hydroxyl groups; but the sugar alcohol derived fromerythrose, i.e., erythritol, contains four hydroxyl groups andaccordingly can be used.) Suitable five hydroxyl group-containingmonosaccharides are galactose, fructose, and sorbose. Sugar alcoholscontaining six -OH groups derived from the hydrolysis products ofsucrose, as well as glucose and sorbose, e.g., sorbitol, are alsosuitable. Examples of disaccharide polyols which can be used includemaltose, lactose, and sucrose, all of which contain eight hydroxylgroups.

Preferred polyols for preparing the polyesters for use in the presentinvention are selected from the group consisting of erythritol, xylitol,sorbitol, glucose and sucrose. Sucrose is especially preferred.

The polyol starting material having at least four hydroxyl groups mustbe esterified on at least four of the -OH groups with a fatty acidcontaining from about 8 to about 22 carbon atoms. Examples of such fattyacids include caprylic, capric, lauric, myristic, myristoleic, palmitic,palmitoleic, stearic, oleic, ricinoleic, linoleic, linolenic,eleostearic, arachidic, arachidonic, behenic, and erucic acid. The fattyacids can be derived from naturally occurring or synthetic fatty acids;they can be saturated or unsaturated, including positional andgeometrical isomers, depending on the desired physical properties (e.g.,liquid of a desired viscosity or solid) of the polyol fatty acidpolyester compound being prepared.

Fatty acids per se or naturally occurring fats and oils can serve as thesource for the fatty acid component in the polyol fatty acid polyester.For example, rapeseed oil provides a good source of C₂₂ fatty acids. TheC₁₆ -C₁₈ fatty acids can be obtained from tallow, soybean oil, andcottonseed oil. Shorter chain fatty acids can be obtained from coconut,palm kernel, and babassu oils. Corn oil, lard, oil, palm oil, peanutoil, safflower seed oil, sesame seed oil, and sunflower seed oil areexamples of other natural oils which can serve as the course of thefatty acid used to prepare the polyesters herein.

Preferred fatty acids for preparing the polyol polyesters herein are theC14 to C18 acids, and are most preferably selected from the groupconsisting of myristic, palmitic, stearic, oleic, and linoleic fattyacids. Thus, natural fats and oils which have a high content of thesefatty acids represent preferred sources for the fatty acid component,i.e., soybean oil, olive oil, cottonseed oil, corn oil, tallow and lard.

The polyol fatty acid polyesters useful in this invention must containat least four fatty acid ester groups. Polyol fatty acid polyestercompounds that contain three or less fatty acid ester groups aredigested in and the products of digestion are absorbed from theintestinal tract much in the manner of ordinary triglyceride fats,whereas the polyol fatty acid polyester compounds that contain four ormore fatty acid ester groups are substantially nondigestible andconsequently nonabsorbable by the human body. It is not necessary thatall of the hydroxyl groups of the polyol be esterified with fatty acid,but it is preferable that the polyester contain no more than twounesterified hydroxyl groups. Most preferably, substantially all of thehydroxyl groups of the polyol are esterified with fatty acid, i.e., thecompound is substantially completely esterified. The fatty acidsesterified to the polyol molecule can be the same or mixed.

To illustrate the above points, a sucrose fatty triester would not besuitable for use herein because it does not contain the required fourfatty acid ester groups. A sucrose tetra-fatty acid ester would besuitable, but is not preferred because it has more than two unesterifiedhydroxyl groups. A sucrose hexa-fatty acid ester would be preferredbecause it has no more than two unesterified hydroxyl groups. Highlypreferred compounds in which all the hydroxyl groups are esterified withfatty acid include the sucrose octa-fatty acid esters.

In any given polyol fatty acid polyester compound the fatty acid estergroups can be selected on the basis of the desired physical propertiesof the compound. For example, the polyol polyesters which containunsaturated fatty acid ester groups and/or a preponderance of shortchain, e.g., C₁₂, fatty acid ester groups are generally liquid at roomtemperature. The polyols esterified with longer chain and/or saturatedfatty acid groups such as stearoyl are solids at room temperatures.

The following are nonlimiting examples of specific polyol fatty acidpolyesters containing at least four fatty acid ester groups suitable foruse in the present invention: glucose tetraoleate, glucosetetrastearate, the glucose tetraesters of soybean oil fatty acids, themannose tetraesters of mixed tallow fatty acids, the galactosetetraesters of olive oil fatty acids, the arabinose tetraesters ofcottonseed oil fatty acids, xylose tetralinoleate, galactosepentastearate, sorbitol tetraoleate, the sorbitol hexaesters of oliveoil fatty acids, xylitol pentapalmitate, the xylitol tetraesters ofsubstantially completely hydrogenated cottonseed oil fatty acids,sucrose tetrastearate, sucrose pentastearate, sucrose hexaoleate,sucrose octaoleate, the sucrose octaesters of partially or substantiallycompletely hydrogenated soybean oil fatty acids and the sucroseoctaesters of peanut oil fatty acids.

As noted above, highly preferred polyol fatty acid esters are thosewherein the fatty acids contain from about 14 to about 18 carbon atomsand are thus derived from such natural materials as soybean oil andolive oil. Examples of such compounds are the erythritol tetraesters ofolive oil fatty acids, erythritol tetraoleate, xylitol pentaoleatesorbitol hexaoleate, sucrose octaoleate, and the sucrose hexa-, hepta-and octaesters of soybean oil fatty acids, partially or substantiallywholly hydrogenated.

The polyol fatty acid polyesters suitable for use herein can be preparedby a variety of methods well known to those skilled in the art. Thesemethods include: transesterification of the polyol with methyl, ethyl orglycerol fatty acid esters using a variety of catalysts; acylation ofthe polyol with a fatty acid chloride; acylation of the polyol with afatty acid anhydride; and acylation of the polyol with a fatty acid, perse. As an example, the preparation of polyol fatty acid esters isdescribed in U.S. Pat. No. 2,831,854, incorporated herein by reference.The most highly preferred methods of preparing the polyol polyestersused herein are disclosed in U.S. Pat. Nos. 4,517,360 and 4,518,772,incorporated herein by reference.

Specific, but nonlimiting, examples of the preparation of polyol fattyacid esters suitable for use in the practice of this invention are asfollows.

Erythritol tetraoleate--Erythritol and a five-fold molar excess ofmethyl oleate are heated at 180° C., under vacuum, with agitation, inthe presence of sodium methoxide catalyst over two reaction periods ofseveral hours each. The reaction product (predominately erythritoltetraoleate) is refined in petroleum ether and crystallized three timesfrom several volumes of acetone at 1° C.

Xylitol pentaoleate--Xylitol and a five-fold molar excess of methyloleate in dimethylacetamide (DMAC) solution are heated at 180° C. forfive hours in the presence of sodium methoxide catalyst, under vacuum.During this time the DMAC is removed by distillation. The product(predominately xylitol pentaoleate) is refined in petroleum ethersolution and, after being freed of petroleum ether, is separated as aliquid layer four times from acetone at ca. 1° C. and twice from alcoholat ca. 10° C.

Sorbitol hexaoleate is prepared by essentially the same procedure usedto prepare xylitol pentaoleate except that sorbitol is substituted forxylitol.

Sucrose octaoleate is prepared by substantially the same procedure asthat used to prepare erythritol tetraoleate except that sucrose issubstituted for erythritol.

The fat-soluble vitamins can optionally be used to fortify the foregoingpolyesters. It will be appreciated that commercial preparations of theappropriate vitamins and/or appropriate vitamin mixtures which providevitamins A, D, E and K can be used herein. See U.S. Pat. No. 4,034,083for details of the role of these vitamins in metabolism and their use incombination with polyesters of the type used in this invention.

In general terms, the vitamins are classified as either "fat-soluble" or"water-soluble". The fat-soluble vitamins are used to fortify thepolyester materials herein. The fat-soluble vitamins include vitamin A,vitamin D, vitamin E, and vitamin K.

The amount of the individual fat-soluble vitamins used to fortify thepresent compositions can vary with the age of the recipient, the dosageregimen used, and the amount of the vitamin ingested from other dietarysources. For example, in younger, growing children or in pregnantfemales it is recognized that larger amounts of any given vitamin shouldbe ingested to supply optimal nutritional benefits than are needed withadult males. If the user of the present compositions happens to ingestfoods which are extremely rich in a given fat-soluble vitamin, less ofthat vitamin need be used in the present compositions to insure adequateintestinal uptake for good nutrition. In any event, an attendingphysician can, if so desired, measure the amount of fat-soluble vitaminsin the plasma. Based on these data, the appropriate type and amount offat-soluble vitamin used to fortify the polyesters herein can then bedetermined on an individual basis.

More simply, the formulator of the compositions herein can fortify thepolyesters with a recommended daily allowance (RDA), or increment ormultiple of an RDA, of any of the fat-soluble vitamins to insure thatthe user of the compositions will maintain a nutritionally adequateuptake of said vitamins. For example, with vitamin A a daily amount inthe range of 20 international units (I.U. to about 57 I.U. per kilogramof body weight can be employed. With vitamin D, fortification of thecompositions to provide about 400 I.U., total, per day is ample. Whensupplementing with vitamin E, the amount of the vitamin optimal fordietary intake ranges from 3-6 I.U. for infants to 25-30 I.U. total, perday, for adults. When supplementing with vitamin K, it is more difficultto estimate the amount to be ingested to provide adequate nutritionsince the microorganisms living in the intestine can synthesize thisvitamin. However, it is known that ingestion of from 0.5 mg.-1 mg. ofvitamin K per day will prevent insufficiency.

METHOD OF TREATMENT

The treatment regimen herein comprises orally administering to a patientin need of having a lowered blood cholesterol level a safe and effectiveamount of the psyllium seed gum, or source thereof, and a nonabsorbable,nondigestible polyol polyester of the type described hereinabove, or,conveniently, mixtures of these two materials. Ingestion of from 1 g to30 g of the psyllium material and from 5 g to 50 g of the polyestermaterial is appropriate in most circumstances. However, this can varywith the size and condition of the patient, and the patient's bloodcholesterol level. Such matters will, of course, be apparent to theattending physician. However, since the psyllium material and the polyolmaterial are nontoxic and nonallergenic, even higher ingestion levelscan be used without undue side effects, keeping in mind that thematerials herein do have a laxative effect.

Treatment of the patient comprises chronic ingestion in order to lowerand maintain the low cholesterol levels. Daily ingestion is preferred,and a daily ingestion of from about 5 g to about 15 g of the psylliummaterial and from about 15 g to about 50 g of the polyester material ismost commonly used, with said ingestion being at two or three regularlyspaced intervals throughout the day. Again, depending on the patient'ssize and cholesterol level in the patient's blood, this can be varied.

The preferred polyol polyesters used in the foregoing methods are:sucrose octaoleate, sucrose octalinoleate, sucrose oltapalmitate andmixtures thereof.

As mentioned, it is convenient to use the psyllium material and thepolyester as a mixture. Thus, psyllium seed husks are prepared in awell-known manner and are admixed with the polyester, generally in aweight ratio of about 10:1 to about 1:10, preferably 3:1 to 1:3,conveniently 1:1. The materials readily admix, particularly when aliquid polyester such as sucrose octaoleate is used, and, at a weightratio of 1:1 the resulting mixed composition has the appearance ofresinous granules. These granules can be compacted to provide tablets orcapsules, or, conveniently, can be spooned-out from the bulk mixture andeither administered by the spoonful or admixed with water and drunk.

The following examples are typical of the compositions of thisinvention, but are not intended to be limiting thereof.

EXAMPLE I

    ______________________________________                                        Ingredient          Amount (grams)                                            ______________________________________                                        Blond psyllium husk (macerated)                                                                   3.8                                                       Sucrose octaoleate  10                                                        Flavor              As desired                                                ______________________________________                                    

The psyllium husk and sucrose octaoleate are blended to form a unit dosecomposition. Three such unit doses are ingested each day, orally, duringthe course of two weeks to lower blood cholesterol. Thereafter, one doseper day is used, on a continuing basis.

EXAMPLE II

    ______________________________________                                        Ingredient       Amount (grams)                                               ______________________________________                                        Psyllium*         7                                                           Sucrose octapalmitate**                                                                        20                                                           ______________________________________                                         *As METAMUCIL brand laxative                                                  **Vitaminized with Vitamin E                                             

The psyllium and sucrose octapalmitate are each taken concurrently, byoral administration, three times per day, to reduce blood cholesterollevels.

It is to be appreciated that the laxative effect of psyllium is enhancedby the polyester materials herein.

EXAMPLE III

    ______________________________________                                        Ingredient         Amount (grams)                                             ______________________________________                                        Psyllium*           7                                                         Sucrose polyester mixture**                                                                      50                                                         ______________________________________                                         *As macerated husks 50:50 with dextrose                                       **Sucrose octaoleate/sucrose octalinoleate mixture                       

The composition of Example III are administered in a single daily doseto reduce blood cholesterol.

While not intending to be limited by theory, it is surmised that theenhanced cholesterol lowering properties of the instant compositions aredue to the differing modes of action of the two ingredients, thepsyllium removing bile acids via the feces and the polyesters dissolvingand removing cholesterol.

What is claimed is:
 1. A composition of matter for reducing bloodcholesterol levels, comprising:(a) psyllium seed gum or source ofpsyllium seed gum; and (b) a nonabsorbable, nondigestible polyolpolyester at a weight ratio of component (a): component (b) from 3:1 to1:3.
 2. A method for reducing blood cholesterol in a patient in need ofsuch treatment, by administering to said patient:(a) psyllium seed gumor a source of psyllium seed gum; and (b) a nonabsorbable, nondigestiblepolyol polyester; or (c) mixtures of (a) and (b); said method comprisingoral ingestion of from 1 g to 30 g of component (a) and from 5 g to 50 gof component (b).
 3. A method according to claim 2 which compriseschronic ingestion.
 4. A method according to claim 3 which comprisesdaily ingestion.
 5. A method according to claim 4 which comprises dailyingestion of from about 5 g to about 15 g of component (a) and fromabout 15 g to about 50 g of component (b), said ingestion being at twoor three regularly-spaced intervals throughout the day.